Protozoans infect and kill millions of people annually. However, in most cases, efficacious chemotherapeutic agents and vaccines are unavailable to treat these diseases.
Human malaria, caused by a protozoan sporozoa, is an acute and chronic protozoal disease caused by four species of plasmodia, namely Plasmodium falciparum, P. vivax, P. ovale and P. malariae. P. falciparum is the most virulent of these and the only one that kills acutely. The plasmodial parasites are transmitted by female mosquitoes of several species of the genus Anopheles. The World Health Organization recognizes malaria as the world's major primary health problem, causing more morbidity and mortality than any other disease. An estimated 300-500 million cases occur annually resulting in 3-5 million deaths, mostly among children. Malaria is a serious problem mainly in the tropical and subtropical world, especially Africa, South and Central America, India and Southeast Asia. Isolated cases of malaria have recently been reported in the southeastern and southwestern United States. The drug chloroquine is often used to treat malaria, however, the rapid spread of chloroquine-resistant P. falciparum and the lack of a malaria vaccine emphasizes the long-felt need to develop new strategies and agents for controlling this disease.
Babesiosis, an infection by protozoan sporozoa of the genus Babesia, is transmitted by hard-bodied ticks. The causative organisms, parasites resembling those of malaria, invade and destroy erythrocytes. Babesia infections in wild and domestic animals occur worldwide and are well known in veterinary medicine. Human infections are more rare and occur exclusively in Europe and North America. In many countries, Babesia is responsible for serious economic losses to the exclusively in Europe and North America. In many countries, Babesia is responsible for serious economic losses to the: livestock industry. No effective chemotherapeutic treatment or vaccine has been known for treatment of babesiosis.
Chagas disease (American trypanosomiasis) is a zoonotic infection caused by the protozoan Trypanosoma cruzi. It affects as many as 15 million people living in South and Central America. African Trypanosomiasis (Sleeping sickness) is a chronic infection with Trypanosoma brucei gambiense or an acute one with T.B. rhodesiense. These hemoflagellate protozoa are transmitted cyclically by several species of blood-sucking tsetse flies of the genus Glossind. There are no efficacious and safe drugs for treating the chronic forms of these infections.
Taxol is a diterpenoid isolated from the stem bark of the western yew, Taxus brevifolia. Taxol is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin. Taxol has been demonstrated to possess antineoplastic activity and has been identified as an anti-cancer agent, particularly in the treatment of advanced ovarian cancer.
Over ten years ago, Baum et al. Proceeding of the National Academy of Science, U.S.A. 1981, 78, 4571-4575, found that taxol inhibited the flagellate protozoan Trypanosoma cruzi. Trypanosomes, being flagellated protozoans, belong to the protozoal Phylum mastigophora. Baum et al. found that the addition of taxol inhibited the replication of T. cruzi in a dose-dependent fashion. Baum et al. treated cultures containing trypanosomes with 1 .mu.M to 10 .mu.M of taxol. However, treatment of trypanosomiasis was never developed and there are presently no efficacious and safe drugs for treating these infections, particularly the chronic forms. Mastigophora, such as the Trypanosoma and Leishmania species, are flagellated protozoans that asexually reproduce by binary fission. This is quite different than the Protozoa Sporozoa, which includes the Plasmodium, Toxoplasma, Isospora, Sarcocystis, Crytosporidium and Pneumocystis species, which reproduce by asexual (schizogony) and sexual (sporogony) multiplication. Another important distinguishing feature of the Mastigophora from the Sporozoa is the unique microtubular cytoskeleton that lies just beneath the plasma membrane of the Mastigophora. Baum et al. suggested that it was the perturbation of this unique submembranous cytoskeletal network by taxol that prevented Trypanosoma cruzi daughter cells to separate during cytokinesis, thus blocking replication. The mode of action of taxol described by Baum et al. is not applicable to the Sporozoa for the reasons described above.
Treatments for malaria and babesiosis have been similarly disappointing. Methods which are known for the treatment of malaria and babesiosis have not been satisfactory due to expense, limited efficacy, drug resistance, and safety. Methods for the treatment of malaria and babesiosis infections are greatly needed. The present invention provides methods satisfying this long-felt need.